Однородные warianty missense w genie CACNB4 powodują epilepsję dziedziczoną autosomalnie recesywnie w dwóch niespokrewnionych pakistańskich rodzinach konsanguicznych

OBJECTIVE: Epilepsy is a heterogeneous group of neurological disorders characterized by recurrent seizures with diverse clinical manifestations. Seizures are classified based on their onset and semiology as focal, generalized, or unknown onset, whereas epilepsy syndromes are defined by specific electroclinical features, age at onset, and etiological factors. In this study, we investigated the diagnostic utility of whole-exome sequencing (WES) in two consanguineous families presenting with epilepsy and neurological manifestations segregating in an autosomal recessive manner. METHODS: Two affected members of family 1 and one affected member from family 2 underwent whole-exome sequencing (WES). The sequencing data were analyzed using an in-house bioinformatics pipeline to identify potential disease-causing variants. Bidirectional Sanger sequencing was performed to examine the co-segregation of the investigated variants. To further evaluate the pathogenicity of the identified variants, 3D protein modeling and several in silico tools were used. RESULTS: We studied two consanguineous families with multiple affected individuals manifesting epilepsy, consistent with autosomal recessive inheritance. WES of family 1 identified a novel homozygous, presumably deleterious, missense variant c.839T>C:p.(Ile280Thr), in CACNB4 (NM_000726.3). Family 2 also harbored a novel homozygous, presumably deleterious, missense variant, c.1199G>A;p.(Arg400His). Both variants affect highly conserved residues. 3D modeling suggested that the mutant proteins required longer time to stabilize and exhibited increased structural flexibility. Both variants resulted in less compact protein structures with an expanded central cavity (∼10 Å larger), thereby altering the overall conformation. SIGNIFICANCE: To our knowledge, this is the second report of autosomal recessive epilepsy associated with biallelic CACNB4 variants. Epilepsy is often a multigenic disorder, which makes clinical diagnosis challenging. Genetic investigations play a crucial role in identifying mutation hotspots, facilitating more accurate diagnoses and enhancing the design of diagnostic panels for early detection.